Dose-dense TPF induction chemotherapy for locally advanced head and neck cancer: A phase II study

Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck (SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN.

Hsieh et al BMC Cancer (2020) 20:832 https://doi.org/10.1186/s12885-020-07347-6 RESEARCH ARTICLE Open Access Dose-dense TPF induction chemotherapy for locally advanced head and neck cancer: a phase II study Ching-Yun Hsieh1, Ming-Yuh Lein1, Shih-Neng Yang2, Yao-Ching Wang2, Yin-Jun Lin2, Chen-Yuan Lin1, Chun-Hung Hua3, Ming-Hsul Tsai3 and Ching-Chan Lin1,4* Abstract Background: Phase studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck (SCCHN) Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN Methods: In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50 mg/m2 on day 1, leucovorin 250 mg/m2 on day1, followed by 48-h continuous infusion of 2500 mg/ m2 of 5-fluorouracil on day and 2, every weeks for cycles followed by radiotherapy The primary endpoint was the response rate (RR) after ICT Results: Fifty-eight patients were enrolled from June 2014 to September 2015 Overall RR after ICT was 89.6% [complete response (CR), 31%; partial response (PR), 58.6%] Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively 94.8% of patients completed all treatment courses of ICT without dose reduction The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%) Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS Conclusions: Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN The presence of CR after ICT predicted long-term survival Trial registration: ClinicalTrials.gov Identifier: NCT04397341, May 21, 2020, retrospectively registered Keywords: Head and neck cancer, Docetaxel, Cisplatin, Fluorouracil, Dose-dense chemotherapy, Induction chemotherapy * Correspondence: linchin13256@gmail.com Division of Hematology and Oncology, Department of internal medicine, China Medical University Hospital, China Medical University, Yude Rd, North District, Taichung 404, Taiwan Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan Full list of author information is available at the end of the article © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data Hsieh et al BMC Cancer (2020) 20:832 Background Chemotherapy combined with radiotherapy (RT) is crucial for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who are inoperable or who require organ preservation It includes concurrent chemoradiotherapy (CRT) and induction chemotherapy (ICT) followed by RT or CRT [1, 2] The most common ICT regimen included cisplatin plus 5-fluorouracil (PF) [3] However, the PF ICT group was inferior to the CRT group in locoregional control and event-free survival [4] To improve the efficacy of ICT, a revolutionary treatment strategy in the recent decade has been the addition of docetaxel to PF ICT Two phase III trials confirmed that TPF ICT provides a significant survival advantage compared with PF ICT [5, 6] However, whether TPF ICT plus CRT may also obtain better survival outcomes than the standard CRT is controversial Two phase III trials showed that TPF ICT plus CRT did not reveal a statistically significant survival benefit compared with CRT alone [7, 8] Furthermore, only a phase III trial of TPF ICT reached the OS benefit compared with the no-induction group [9] The most significant clinical concern is the more severe adverse events especially of grade 3/4 neutropenia, and TPF-related deaths, which may compromise treatment efficacy [10] In the TPF regimen, 75 mg/m2 of docetaxel every weeks is a widespread prescription based on the TAX 323 study [5] However, the toxicities of triweekly docetaxel have attracted a lot of worries especially for the elderly patients and the Asian population [11, 12] In a prospective pharmacokinetic study of 75 mg/m2 docetaxel every weeks for patients with solid tumors, 63% of elderly patients experienced grade neutropenia compared to 30% of younger patients [12] The analysis from published data of phase II and III clinical trials showed that a higher incidence of docetaxel-induced grade 3/4 neutropenia in Asian clinical studies than the non-Asian studies (odds ratio 19.0, [13]) In addition, hematologic toxicity still occurs in these patients even with the reduced dose of triweekly TPF [14, 15] Therefore, although TPF regimen is an effective regimen for patients with SCCHN, the optimal scheduling remains unclear One of the promising alternatives is the dosedense chemotherapy regimen, which can be reached by the same dose intensity administered at a shorter timeinterval, for instance at a biweekly interval Dose-dense chemotherapy does not mean greater toxicity In fact, the experience from the C9741 trial for patients with breast cancer showed that more dose-dense administration was associated with less neutropenia and less need for hospitalization due to febrile neutropenia [16] In terms of SCCHN, to the best of our knowledge, only one retrospective study reported the biweekly modified TPF chemotherapy was safe and was as Page of effective as triweekly TPF [17] However, the decreased dose-intensity of cisplatin and docetaxel in this study made the interpretation of the study difficult when compared to the “classical “triweekly TPF regimen Additionally, the clinical trials in bladder and breast cancers have shown that the benefit of a dose-dense approach in the neoadjuvant setting, but the studies had not been explored in SCCHN [18] Therefore, we designed a phase II study to evaluate the efficacy and toxicity of the biweekly dose-dense TPF Methods Patients This prospective single-arm phase II trial enrolled the patients with newly diagnosed locally advanced SCCHN The study was conducted in accordance with the World Medical Association Declaration of Helsinki (version 2002) and was approved by the China Medical University Hospital Review Board (CMUH103-REC2–038) Patients provided IRB-approved, protocol-specific written informed consent prior to initiating therapy for studyspecific treatment and inclusion in the present study The study was retrospectively registered in ClinicalTrials.gov (Identifier: NCT04397341) The inclusion criteria were as follows: (1) histopathologically confirmed diagnosis of AJCC 7th edition stage or unresectable squamous cell carcinoma of the oral cavity, larynx, oropharynx, or hypopharynx; (2) age > 20 years; (3) ECOG performance status, 0, 1, or at study entry; and (4) adequate organ function The exclusion criteria were as follows: (1) previous chemotherapy or RT for SCCHN, (2) previous or concurrent malignancy, and (3) peripheral neuropathy > grade Additionally, patients were defined as having an unsuitable condition for radical surgery after the evaluation of a multidisciplinary team The inoperability criteria included very advanced T stage (T4b) (tumor invasion into the cervical vertebra, carotid artery, or fixed lymph nodes), risk of significant postoperative dysfunction, and low surgical curability (T3–T4, N2–N3) Treatment Patients received ICT after enrollment The chemotherapy regimen was delivered with docetaxel 50 mg/m2 on day 1, cisplatin 50 mg/m2 on day and 5-fluorouracil 2500 mg/m2 by continuous infusion over 46 h on Day 1–2 Moreover, the treatment was administered every 14 days for cycles or until disease progression or intolerant treatment toxicity In our study, primary G-CSF support was not allowed, but G-CSF administration can be used when the patients had febrile neutropenia or grade neutropenia The dose modification was allowed, which was according to the greatest degree of toxicity that was graded by Hsieh et al BMC Cancer (2020) 20:832 NCI-CTCAE Version 4.03 Also, the dose modification of study treatment could be according to the investigator’s experiences Radiotherapy was administered using the sequential Intensity-Modulated Radiotherapy (IMRT) for 1.8–2.0Gy per fraction with five daily fractions per week for weeks Two clinical target volumes (CTVs) were designed for risk stratification: CTV1, encompassing the gross tumor volume (GTV) of a primary tumor, metastatic lymph nodes, and regions adjacent to the GTV; and CTV2, encompassing the ipsilateral or contralateral N0 regions at risk of microscopic tumor During the first course, a dose of 50.4–54.0Gy was included in CTV1 and CTV2 During the second course, a boost of 16.2– 21.6Gy was included in CTV1 The median cumulative dose of 70.2 and 54.0Gy was achieved in CTV1 and CTV2, respectively Concurrent chemotherapy with weekly cisplatin 35 mg/m2 was recommended during the period of radiotherapy However, it is allowed to give radiotherapy alone or substitute cetuximab for cisplatin as the radiosensitizer for the patients not suitable for concurrent chemoradiotherapy by the assessment and discretion of the attending physician Cetuximab was used at a 250 mg/m2 on a weekly basis (400 mg/m2 as the initial dose) for seven times Study design, end point definition, and statistical considerations This was a phase II, single-center, prospective clinical trial to evaluate the induction chemotherapy (ICT) with a biweekly dose-dense TPF regimen for SCCNHN patients The primary endpoint of the study was the response rate (RR) of ICT, while the secondary ones included response rate (RR) of the total treatment, progression-free survival (PFS), overall survival (OS), and toxicity and safety of the treatment “The response assessment of ICT (the primary endpoint) was performed using CT scan at the end of treatment according to the RECIST 1.1 criteria Positron emission tomography (PET)/CT scan was also performed to evaluate the response according to the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria.” In addition, only when CT scans failed to reveal an obvious primary, PET/CT scan was used to confirm the complete response The response assessment of the total treatment was performed at 10–12 weeks since the end of radiotherapy with CT scan, and the response assessment was confirmed by repeat CT scan at an interval of 6–8 weeks Then, the CT scan was performed every 3–4 months in the first years and every 6–7 months until progression The PFS was defined as the time from the study registration date to the first day of disease progression at any site or of death by any cause The OS was defined as the time from the date of study Page of registration to the date of death, or the last confirmed survival date The toxicity was recorded by the investigators using the National Cancer Institute Common Toxicity Criteria scale version 4.03 (NCI-CTCAE Version 4.03) Toxicities were assessed at each weekly visit during ICT and at the end of treatment At the time of study design, the response rate of standard triweekly TPF regimen was reported to be 68 and 72%, respectively [5, 6] Therefore, the study was conducted using Simon’s optimal two-stage phase II design based on response rate for sample-size calculation A sample size of 35 patients was required to accept the hypothesis that the true response rate was greater than 90% with a 90% power and to reject the hypothesis that the response rate was less than 70% with 5% significance Initially, we planned to enroll 15 patients in the first stage If 11 or more responses were observed, we planned to continue to the second stage for a total of 35 patients in the analysis Assuming a dropout rate of 10%, the total number of enrolled patients needed was calculated to be 40 If the endpoints were achieved, we will extend the number of enrolled patients to 60 for translation study The translational study aims to study the prognostic significance of the metabolic parameters of PET in tumour response to ICT Kaplan-Meier survival analysis was used to estimate survival endpoints, and the log-rank test was used to compare the differences between curves All tests are two-sided, and a p-value < 0.05 was considered to indicate a statistically significant difference Multivariate analysis was carried out using a Cox proportional hazards regression model The age was classified into > 50 and ≦50 years old using the receiver operating characteristic (ROC) curve Statistical analysis was performed with the SPSS software (version 17.0; SPSS, Chicago, IL) and EZR version 1.32 software [19] Results Patients At the first stage of the study, thirteen of 15 patients achieved better than stable disease after ICT treatment As a consequence, twenty-five patients were further enrolled in the second stage Overall thirty-five of 40 patients were evaluated to be responders to ICT The response rate was estimated to be 87.5% Finally, a total of 60 patients were enrolled in the study from June 2014 to September 2015 Among the 60 patients, only fiftyeight patients were assessable because one patient was excluded because of ineligibility and one withdrew the consent (Fig 1) The clinical characteristics of the patients were demonstrated in Table The median follow-up time was 31.8 months (from 1.4 to 43.6 months) The median age is 53 years old (from 28 to 69 Hsieh et al BMC Cancer (2020) 20:832 Page of Unresectable stage IV squamous cell carcinoma of head and neck (N=60) did not receive dose-dense TPF was ineligible withdraw concent 58 were assigned to receive cycles of dose-dense TPF received < cycles of treatment had disease progression escaped 55 completed cycles of treatment 56 were evaluable for resonse rates and adeverse effects refused the following radiotherapy 54 were assigned to receive the following radiotherapy 24 received chemoradiotherapy 16 received cetuximab/radiotherapy 14 received radiotherapy alone 54 were evaluable for response rates and survival Fig Enrollment and outcomes years old) All of them had stage IV SCCHN (IVA, 60.3%; IVB, 39.7%, AJCC 7th edition) The primary site of oral cavity/oropharynx/hypopharynx was 31.0%/ 43.1%/25.9% Initially, all of the patients were recruited by AJCC 7th edition, but the stage status was analyzed later according to AJCC 8th edition Six of 25 (24%) patients with oropharyngeal cancer (OPC) were considered HPV-associated by the immunohistochemical stain of p16, and 19 (76%) patients were HPV negative Most patients reported the history of drinking and smoking Efficacy and outcome All the 58 patients received ICT with biweekly TPF Fifty-five of 58 (94.8%) patients completed all treatment courses of ICT Three patients did not complete the 6cycle treatment including two who escaped during ICT and the other one had early disease progression The mean accumulative dose of docetaxel, cisplatin and 5fluorouracil was 288 mg/m2, 288 mg/m2, and 14,474 mg/m2, respectively Therefore, the relative dose intensity was 96, 96 and 96.5%, respectively No dose reduction occurred in all of the patients administered with ICT Four patients had dose delay of more than days because of infection The response rates (RR) of ICT was shown in Table On CT scan, 12 of 58 (20.7%) patients achieved the complete response, but on PET/ CT scan, 18 (31%) had the metabolic CR (CR) Three patients achieved a stable disease (SD) and 34 patients had a partial response (PR) The overall RR of ICT was 89.7% All of the patients received full-dose ICT, and none had the reduced dose of docetaxel, cisplatin, or 5-fluorouracil Hsieh et al BMC Cancer (2020) 20:832 Page of Table Clinical characteristics of the patients Characteristics N = 58 Number percentage Table Response to induction chemotherapy and to total treatment of induction therapy plus radiotherapy Number Age,median (range): 53 (28–69) Percentage Response of Induction chemotherapy (N = 58) < 50 16 27.6 50–65 40 69.0 Overall RR ≥ 65 3.4 CR 18 31.0% PR 34 58.6% 93.1 SD 5.2% 6.9 PD 5.2% Gender Male Female 54 52 89.7% Response of ICT plus RT (N = 54) ECOG performance status 37 63.8 Overall RR 42 21 36.2 CR 37 68.5% PR 9.3% Smoking SD 11.1% Yes PD 11.1% No 49 84.5 15.5 Yes 44 75.9 No 14 24.1 Yes 43 74.1 No 15 25.9 III (HPV+ oropharynx) 10.3 IVa 13 22.4 IVb 39 67.3 1,2 13 22.4 15.5 4a 13 22.4 4b 23 39.7 8.6 (HPV+ oropharynx) 5.2 77.8% CR complete response, ICT induction chemotherapy, PR partial response, PD progressive disease, RR response rate, RT radiotherapy, SD stable disease Alcohol drinking Betal nut chewing Stage (AJCC 8th edition) T N 2b 14 24.1 2c 11 19.0 25 43.1 Site Oral cavity 18 31.0 Oropharynx 25 43.1 HPV associated 10.4 HPV negative 19 32.7 15 25.9 Yes 13.8 No 50 86.2 Hypopharynx Neck dissection after ICT After ICT, patients refused the following radiotherapy Twenty-four patients received chemoradiotherapy, 16 patients received cetuximab/RT, and 14 patients received RT alone Therefore, a total of 54 patients is evaluable for treatment response after radiotherapy Three of 54 (5.5%) cannot complete the RT program because that one patient had severe pneumonia, another developed ischemic stroke during the treatment, and one escaped from the treatment protocol After the CRT or RT process, 37 (68.5%) patients achieved CR, (9.3%) had a PR, (11.1%) had a stable disease, and (11.1%) had disease progression The overall RR of the total treatment was 77.8% The 3-year OS and PFS were 56.3% (95%CI, 41.6– 68.6%) and 34.3%, (95%CI, 22.0–46.9%), respectively, as seen in Fig 2a and b The 3-year local-recurrence free survival was 48.4% (95%CI, 34.1–46.9%) and the 3-year metastasis free-survival was 85.6% (95%CI, 71.9–93.0%), as seen in Fig 2c and d We also analyzed the association between tumour response (RR) of ICT and the survival outcomes of the patients The Kaplan–Meier analysis showed that the patients with complete response had superior survival to those with partial response and nonresponders The 3year OS and PFS were 81.7% (95%CI, 53.1–93.8%) and 59.3% (95%CI,33.0–78.1%) in patients with complete response (p value < 0.001) and 45.9% (95%CI,27.4–62.6%) and 25.5% (95%CI,11.9–41.4%) in patients with partial response (p value < 0.001), respectively, as seen in Fig All patients with the response less than PR passed away within 20 months We also performed the multivariate analysis to consider other variables, including age, stage, primary site, and smoking status We did not include HPV status in Cox regression analysis because only Hsieh et al BMC Cancer (2020) 20:832 Page of Fig Survival analsysis a Overall survival b Progression-free survival c Local recurrence-free survival d Metastasis-free survival Discussion Our study showed that biweekly dose-dense TPF ICT in locally advanced SCCHN had a promising treatment response The overall response rate and complete response rate were 89.7 and 31%, respectively The 3-year OS and PFS were 56.3 and 34.3%, respectively Compared to the data from TAX323 and TAX324 trials, standard triweekly TPF ICT regimen achieved 68 and 72% postinduction RR, respectively [5, 6] The 3-year OS and PFS for patients in TAX 323 were 37 and 17%, and those in TAX 324 were 62.0 and 49.0%, respectively [5, 6] Particularly, 25.9% of the grade 3–4 neutropenia in our study is markedly lower than previously reported For example, TAX323 trial reported 76.9% of the grade 3–4 patients were HPV-associated The results showed that response status after ICT was the only significant prognostic factor for OS and PFS (Table S1) Treatment-related adverse events The treatment-related adverse events during ICT are shown in Table During this, mucositis was the most common event (33/58, 56.9%), but only one patient suffered from grade mucositis In grade 3/4 adverse events, 15 patients (25.9%) had neutropenia, and (10.3%) developed febrile neutropenia Also, 11 patients developed infection; however, no patients died during the process A B p